Molecular genomics of bladder cancer

Bladder cancers are heterogeneous at the molecular level with two distinct oncogenic pathways.

Recent genomic and molecular studies have been focused on muscle invasive bladder cancer (MIBC).

Molecular classification based on genetic and molecular alterations characterized by multiple platforms has been proposed for MIBC.

Molecular classification is useful for prognostication and therapy response prediction.

Urothelial cancer (UC) develops via two distinct but somewhat overlapping pathways, papillary and nonpapillary, with low-grade intraurothelial neoplasia (LGIN) as the incipient lesion.

Papillary pathway

• Accounts for approximately 80% of UC

• LGIN progresses to low-grade and then high-grade papillary UC

• Enriched with FGFR3 mutations

• The tumors are often multifocal, superficial, exophytic papillary lesions.

• The tumors frequently recur after local excision.

• The tumors usually do not invade the bladder wall or metastasize.

Nonpapillary pathway

• Accounts for the remaining 20% of UC

• LGIN progresses to UC in situ and then to high-grade invasive UC

• Enriched with TP53 and RB1 mutations

• The tumors are usually solid, nonpapillary lesions

• The tumors often invade the bladder wall and metastasize

• Patients usually do not have a previous history of papillary UC

The overlap between the two pathways

• 10%–15% of papillary UC eventually progress to high-grade invasive UC.

• Often preceded by the development of UC in situ within papillary UC or in the adjacent bladder mucosa.